Human coronavirus NL63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry

Abstract

Coronavirus (CoV) infection of humans is usually not associated with severe disease. However, discovery of the severe acute respiratory syndrome (SARS) CoV revealed that highly pathogenic human CoVs (HCoVs) can evolve. The identification and characterization of new HCoVs is, therefore, an important task. Recently, a HCoV termed NL63 was discovered in patients with respiratory tract illness. Here, cell tropism and receptor usage of HCoV-NL63 were analyzed. The NL63 spike (S) protein mediated infection of different target cells compared with the closely related 229E-S protein but facilitated entry into cells known to be permissive to SARS-CoV-S-driven infection. An analysis of receptor engagement revealed that NL63-S binds angiotensin-converting enzyme (ACE) 2, the receptor for SARS-CoV, and HCoV-NL63 uses ACE2 as a receptor for infection of target cells. Potent neutralizing activity directed against NL63-but not 229E-S protein was detected in virtually all sera from patients 8 years of age or older, suggesting that HCoV-NL63 infection of humans is common and usually acquired during childhood. Here, we show that SARS-CoV shares its receptor ACE2 with HCoV-NL63. Because the two viruses differ dramatically in their ability to induce disease, analysis of HCoV-NL63 might unravel pathogenicity factors in SARS-CoV. The frequent HCoV-NL63 infection of humans suggests that highly pathogenic variants have ample opportunity to evolve, underlining the need for vaccines against HCoVs.C oronaviruses (CoVs) are enveloped RNA viruses that are grouped according to genome sequence and serology (1). Human CoVs (HCoVs) 229E and OC43 are members of groups I and II, respectively, and infection with these viruses is thought to be responsible for Ϸ30% of common-cold cases (1). In contrast, infection with severe acute respiratory syndrome (SARS)-CoV causes a severe respiratory tract illness (RTI) that is fatal in Ϸ10% of infected individuals (2, 3). The factors that determine the pathogenicity of CoVs are incompletely understood; however, a role for the spike (S) protein has been suggested (4). The S proteins of CoVs, which provide virions with a corona-like appearance, mediate infection of target cells and play a central role in viral replication (4). The interaction of CoV S proteins with specific cellular receptors determines, to a large extent, which cells can be infected (5), and the entry process is an attractive target for antiviral therapy (6).Recently, a HCoV termed NL63 was discovered in infants and immunocompromised adults with RTI (7, 8). HCoV-NL63 is a group I CoV and is most closely related to HCoV-229E (7-9). HCoV-229E employs CD13 (aminopeptidase N) as a receptor for infection of target cells (10,11). Because the NL63-and 229E-S proteins share 56% amino acid identity (7), it is conceivable that HCoV-NL63 also engages CD13 for infectious cellular entry. However, the HCoV-NL63-S protein contains a unique, 179-aa sequence at its N terminus that does not share homology with other known CoV proteins and that might alter the re...

Identification of residues in the receptor-binding domain (RBD) of the spike protein of human coronavirus NL63 that are critical for the RBD–ACE2 receptor interaction

“…As all previously known group I coronaviruses use the APN of their own host species as functional receptors (Tresnan & Holmes, 1998;Tresnan et al, 1996), and viral sequence analysis indicates that NL63 is most closely related to 229E (van der Hoek et al, 2004), it has been proposed that NL63 may also employ hAPN as its receptor. However, hACE2 is a functional receptor for NL63 (Hofmann et al, 2005). This finding was quite surprising given that the S protein of NL63 shows only limited sequence similarities to that of SARS-CoV.…”

Physiology of Kidney Renin

“…However, ACE2 deletion worsens the severe acute lung injury induced by acid aspiration or sepsis, and the injection of recombinant human ACE2 attenuates the acute lung failure in the ACE2 knockout as well as wild-type mice (372). In addition, ACE2 is a well-described receptor for the severe acute respiratory syndrome coronavirus (SARS-CoV) and for the human coronavirus-NL63 (348,515). The SARSCoV infection can be attenuated by soluble ACE2 molecules, ACE2 antibodies, and the genetic deletion of ACE2 (304,472,515).…”

Infection with human coronavirus NL63 enhances streptococcal adherence to epithelial cells

“…Human coronavirus NL63 (HCoV-NL63) is a relatively recently discovered human respiratory pathogen with a high worldwide prevalence (Fouchier et al, 2004;Golda & Pyrc, 2008;Hofmann et al, 2005;Pyrc et al, 2004Pyrc et al, , 2006Pyrc et al, , 2007aPyrc et al, , b, 2008Schildgen et al, 2006;van der Hoek et al, 2004. Arguably, HCoV-NL63 is among the most clinically important human coronaviruses and is associated with upper and lower respiratory tract infections, occurring most frequently in the winter season and presenting more severe symptoms in children, the elderly and immunocompromised patients (Bastien et al, 2005;Chiu et al, 2005;Dijkman et al, 2008;Kaiser et al, 2005;Suzuki et al, 2005;Vabret et al, 2005;Wu et al, 2008).…”

“…Human coronavirus NL63 (HCoV-NL63) is a relatively recently discovered human respiratory pathogen with a high worldwide prevalence (Fouchier et al, 2004;Golda & Pyrc, 2008;Hofmann et al, 2005;Pyrc et al, 2004Pyrc et al, , 2006Pyrc et al, , 2007aPyrc et al, , b, 2008Schildgen et al, 2006;van der Hoek et al, 2004 (Fig. 1a).…”